TY - JOUR
T1 - JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants
AU - Sundqvist, Emilie
AU - Buck, Dorothea
AU - Warnke, Clemens
AU - Albrecht, Eva
AU - Gieger, Christian
AU - Khademi, Mohsen
AU - Lima Bomfim, Izaura
AU - Fogdell-Hahn, Anna
AU - Link, Jenny
AU - Alfredsson, Lars
AU - Søndergaard, Helle Bach
AU - Hillert, Jan
AU - Barcellos, Lisa
AU - Booth, David
AU - McCauley, Jacob L.
AU - Comabella, Manuel
AU - Compston, Alastair
AU - DAlfonso, Sandra
AU - De Jager, Philip
AU - Fontaine, Bertrand
AU - Goris, An
AU - Hafler, David
AU - Haines, Jonathan
AU - Harbo, Hanne F.
AU - Hauser, Stephen L.
AU - Hawkins, Clive
AU - Hemmer, Bernhard
AU - Hillert, Jan
AU - Ivinson, Adrian
AU - Kockum, Ingrid
AU - Martin, Roland
AU - Boneschi, Filippo Martinelli
AU - Oksenberg, Jorge
AU - Olsson, Tomas
AU - Oturai, Annette
AU - Patsopoulos, Nikolaos
AU - Pericak-Vance, Margaret
AU - Saarela, Janna
AU - Sawcer, Stephen
AU - Spurkland, Anne
AU - Stewart, Graeme
AU - Zipp, Frauke
AU - Oturai, Annette B.
AU - Hemme, Bernhard
AU - Kockum, Ingrid
AU - Olsson, Tomas
N1 - Funding Information:
Tomas Olsson has received lecture and or advisory board honoraria from BiogenIdec, Novartis, Genzyme and Merck. The same companies have provided unrestricted MS research grants. Bernard Hemmer has received lecture and advisory board honoraria from Biogenidec, Novartism Bayer, Teva, Roche, Glaxo-Smith-Kline, Chugai and Merck-Serono. Biogenidec, Novartis, Metanomics, 5Prime, Roche, Bayer and Merck-Serono have supported the Department of Neurology of the Technische Universität München with research grants. This does not alter our adherence to all PLOS policies on sharing data and materials.
PY - 2014/4
Y1 - 2014/4
N2 - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.
AB - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.
UR - http://www.scopus.com/inward/record.url?scp=84901344743&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1004084
DO - 10.1371/journal.ppat.1004084
M3 - Article
C2 - 24763718
AN - SCOPUS:84901344743
SN - 1553-7366
VL - 10
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 4
M1 - e1004084
ER -
